Free-standing biodegradable patch

ABSTRACT

Methods and apparatus for a free-standing biodegradable patch suitable for medical applications, especially intravascular, minimally-invasive and intraoperative surgical applications are provided, wherein the patch comprises a free-standing film or device having a mixture of a solid fibrinogen component and a solid thrombin component that, when exposed to an aqueous environment, undergoes polymerization to form fibrin. In alternative embodiments the patch may comprise a solid fibrinogen component, with or without an inorganic calcium salt component. The patch may take a non-adherent form during delivery to a target location within a vessel or tissue, and thereafter may be activated to adhere to vessel wall or tissue, and may include a number of additives, including materials to improve the mechanical properties of the patch, or one or more therapeutic or contrast agents.

I. CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation patent application of U.S. patentapplication Ser. No. 14/054,653, filed Oct. 15, 2013, now U.S. Pat. No.9,072,681, which is a divisional patent application of U.S. patentapplication Ser. No. 12/885,306, filed Sep. 17, 2010, now U.S. Pat. No.8,563,510, which claims the benefit of priority of U.S. provisionalpatent application Ser. No. 61/243,979, filed Sep. 18, 2009, the contentof each of which is incorporated herein by reference in its entirety.This application is also related to U.S. patent application Ser. No.12/885,322, filed Sep. 17, 2010, now U.S. Pat. No. 8,529,941, thecontent of which is incorporated herein by reference in its entirety,which claims the benefit of priority of U.S. provisional patentapplication Ser. No. 61/243,979, filed Sep. 18, 2009.

II. FIELD OF THE INVENTION

The present invention relates generally to patches for vessel and organrepair and drug delivery, including free-standing biodegradable patches.

III. BACKGROUND OF THE INVENTION

As some of the leading causes of death in the United States,cardiovascular diseases affect millions. Some diseases result in theweakening of blood vessels, while others result from the stenosis of ablood vessel. Stents have been used to provide support and drug-deliveryto these blood vessels, but stent implantation carries a number ofrisks. For example, blood clots may develop at the site of the stent asthe body rejects the foreign object, or the stent itself may migrate orfracture. As such, alternative methods of providing support to weakenedblood vessels may be desirable.

Another prominent cause of cardiac ischemia and stroke is the occurrenceof vulnerable plaque deposits that can accumulate within an individual'svasculature. Such plaque deposits result when a lipid pool forms beneatha thin fibrous cap along the lining of a vessel. When subjected toincreased rates of hemodynamic pulsating expansion during systole andelastic contraction during diastole associated with excessive exercise,high mechanical stresses may form in the fibrous cap. Such stresses maylead to rupture of the fibrous cap, releasing a shower of potentiallylife-threatening emboli into the patient's vasculature. It wouldtherefore be desirable to provide apparatus and methods for isolatingand treating vulnerable plaques, so as to minimize the risk of suddenrupture.

A number of solutions have been proposed in the prior art for treatingweakened vessels and vulnerable plaques, often involving the placementof a stent within the vessel, with or without a drug-eluting coating.Most stents employ a metal alloy framework, which may include adrug-eluting coating. As noted above, the use of metal stents canintroduce additional long-term concerns for patients, including theoccurrence of endothelial hyperplasia at the ends of the stent, fatiguefracture and stent migration. More recently, drug-eluting coatings havebeen employed on some stent designs to reduce the incidence ofrestenosis, although long-term reduction of restenosis using suchcoatings has yet to be achieved.

In addition, some previously-known stents have sought to employnaturally occurring biodegradable materials, such as fibrin, orsynthetic polymers, such as polyglycolic acid. For example, U.S. Pat.No. 5,510,077 to Dinh et al. describes a stent cast from fibrin bycharging a solution of fibrinogen and a fibrinogen-coagulating protein,such as thrombin, in liquid form into a mold cavity containing a metalalloy frame, so as to form a fibrin-coated stent when the fibrin cures.That patent discloses that synthetic polymers, and/or drugs,additionally may be mixed and cross-linked with the fibrinogen andthrombin to improve tissue ingrowth and neointimal formation as thefibrin degrades. However, the patent does not alleviate concernsregarding the fate of the metal alloy frame once the fibrin fullydegrades. Moreover, it is believed that such coatings may be relativelyfragile, and therefore subject to cracking and delamination resultingfrom bending and torsional stresses applied to the metal alloy frame insitu.

U.S. Pat. No. 5,591,224 to Schwartz et al. and U.S. Pat. No. 6,312,457to DiMatteo et al. attempt to overcome the shortcomings of thepreviously-known devices, such as those described in the Dinh patent,using a support structure formed of elastin, polyglycolic acid or otherbiodegradable polymer instead of a metal alloy frame. DiMatteo alsodescribes that a fibrin layer on the exterior of the device may be usedas an adhesive to adhere the device to the vessel wall. Such materials,however, can be relatively difficult to handle and to deliver within thevasculature using conventional delivery systems, and accordingly nocommercially practicable products have been realized using suchconstructions. Likewise, U.S. Pat. No. 7,399,483 to Stimmeder describescompositions suitable for tissue gluing, sealing or hemostasis, in whicha composition of solid fibrinogen and solid thrombin is disposed on abiodegradable carrier, such as a collagen sponge. Such products are notintended for intravascular use and continue to require some form ofsupport structure.

A number of previously known systems have been investigated that couldenable an adhesive-coated stent or vascular patch to be deliveredintravascularly. For example, U.S. Pat. No. 7,044,982 to Millbockerdescribes methods of repairing internal defects involving anadhesive-coated prosthetic in which the adhesive is encapsulated withina water soluble material so as to be non-adhesive until the prostheticis placed in contact with tissue. U.S. Pat. No. 7,402,172 to Chin et al.describes an adhesive-coated intraluminal therapeutic patch having awater soluble coating and a slidable sheath disposed on the deliverycatheter to prevent premature activation of the adhesive. To date, thesystems described in the foregoing patents do not appear to haveovercome the problems inherent in intravascularly delivering an adhesivepatch without premature or incomplete activation of the adhesive.

IV. SUMMARY OF THE INVENTION

In view of the foregoing, the present invention is directed to methodsand apparatus for providing a free-standing biodegradable patch suitablefor medical applications, especially intravascular, minimally-invasiveand intraoperative surgical applications. In one preferred embodiment,the patch comprises a free-standing film or device comprising a mixtureof a solid fibrinogen component and a solid thrombin component that,when exposed to an aqueous environment, undergoes polymerization to formfibrin. The solid fibrinogen and thrombin components may comprise amixture that forms a continuous layer or may be divided into a pluralityof discrete segments. Alternatively, the solid fibrinogen and solidthrombin components may comprise separate layers. In some embodiments,the patch comprise only solid fibrinogen, or solid fibrinogen with acalcium chloride, but without a thrombin component. In accordance withone aspect of the invention, the film or device may take a non-adherentform during delivery to a target location within a vessel or tissue, andthereafter activated to adhere to a vessel wall or tissue.

A patch constructed in accordance with the principles of the presentinvention may include one or more polymers added to the solid fibrinogenand, if present, thrombin components to improve the mechanicalproperties of the patch, such as strength and/or flexibility. The patchof the present invention optionally may include one or more additionalagents or additives. e.g., Factor XIII. Inorganic calcium salts, aplasticizer, radiopaque material, etc. Some embodiments of the patch ofthe present invention may include one or more therapeutic drugs, genes,or other bioactive agents that elute from the patch into the adjacenttissue or vessel, or are delivered to the surrounding tissue orbloodstream during biodegradation of the patch.

In some embodiments, the patch may be configured for intravascular orminimally-invasive surgical applications to be delivered using anexpandable member (e.g., a balloon, cage, or other expandablestructure), such that the expandable member may be expanded in situ toplace the patch in apposition with tissue or vessel wall. In otherembodiments, the patch may be coated or cast directly onto theexpandable member. In accordance with another aspect of the invention, aprotective layer may be used to temporarily adhere the patch to anexpandable member or a protective layer may applied directly to theexterior of the patch.

In accordance with one aspect of the present invention, the patch may bedisposed on an expandable member such that only those portions of thepatch that contact a tissue or vessel wall by expansion of an expandablemember adhere to the tissue or vessel wall, while non-contactingportions remain affixed to the expandable member. In this manner, thepatch may be used to provide a protective layer to the inner lumen of avessel in the vicinity of a vessel bifurcation without occluding abranch vessel.

Methods of making and using a free-standing biodegradable patch inaccordance with the present invention are provided.

V. BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic view of a first illustrative embodiment of a patchof the present invention.

FIG. 2 is a schematic view of an alternative illustrative embodiment ofa patch of the present invention wherein the constituents are arrangedin separate layers.

FIG. 3 is a schematic view of another alternative illustrativeembodiment of a patch of the present invention in which a mixture ofsolid fibrinogen and solid thrombin components is sandwiched betweenprotective layers.

FIG. 4 is a schematic view of another alternative illustrativeembodiment of a patch of the present invention wherein discrete segmentsof the mixture of solid fibrinogen and solid thrombin components areembedded in a water soluble protective layer.

FIGS. 5A-5D are, respectively, a schematic view of a further alternativeembodiment of the patch of present invention wherein discrete segmentsof the mixture of solid fibrinogen and solid thrombin components arearranged on a protective layer, and illustrative views showingapplication of the patch of FIG. 5A to a target location.

FIGS. 6A-6E are illustrative configurations for articles formed from amixture of solid fibrinogen and solid thrombin components, or solidfibrinogen, prepared in accordance with the present invention.

FIGS. 7A and 7B illustrate one method by which a patch of the presentinvention may be affixed to a balloon catheter.

FIGS. 8A and 8B illustrate an alternative balloon catheter that may beused to deliver the patch of the present invention.

FIGS. 9A-9E illustrate a method of deploying the patch of the presentinvention in a vessel.

VI. DETAILED DESCRIPTION OF THE INVENTION

The present invention is generally directed to a free-standingbiodegradable patch for use in medical procedures for supporting,protecting or joining weakened tissue or vessels, includinginterventional, minimally-invasive and intraoperative surgicalprocedures. The patch of the present invention also may be used forisolating, occluding and/or treating deposits of vulnerable plaque,aneurysms and fistulas.

In accordance with one aspect of the invention, the patch mayincorporate therapeutic drugs, genes or other bioactive agents that areeluted into the surrounding tissue to provide localized treatment orinto an adjacent bloodstream to provide systemic treatment.Alternatively, such drugs, genes or other bioactive agents may bereleased into surrounding tissue or an adjacent bloodstream as the patchbiodegrades. The patch of the present invention also may include one orradiopaque materials to enhance visibility and placement of the patchduring deployment. The patches described herein may be delivered to aportion of the body using one or more delivery systems, which are per seknown. In some embodiments, the delivery system may comprise one or moreexpandable members (e.g., an expandable cage, a balloon, and the like),as described herein below.

In accordance with one aspect of the present invention, free-standingbiodegradable patches are provided that function beneficially whendelivered in the body. For example, the patch may provide mechanicalsupport to tissue, such as where a patch is delivered intraluminally tothe interior of a blood vessel to prevent restenosis or narrowing of theblood vessel. In other contexts, the inventive patch may be deployed ina vessel to seal and support a dissection in a vessel wall caused byballoon dilatation. In patients that have suffered an aneurysm, theinventive patch may be used to isolate and/or stabilize a weakenedvessel wall.

The patches of the present invention additionally may provide a sealingor holding function. For example, a patch constructed in accordance withthe present invention may be used to seal a perforation in a bloodvessel or other hollow body organ, such as may arise during apercutaneous procedure. In other instances, a patch may be used to seala vulnerable plaque, thereby allowing drugs to be delivered to theplaque to stabilize or dissipate the plaque without damaging the thinfibrous cap. In such applications, the patch also may promoteendothelialization of the lesion. In still other instances, the patchmay be employed to retain two tissue surfaces in apposition, forexample, to secure two vessels that are joined during an anastomosis.

In accordance with another aspect of the invention, the patch of thepresent invention additionally aids in endothelialization (i.e., theprocess of tissue regrowth over a stent or other foreign body). Inparticular, the inventive patch will form a fibrin matrix in situ, thusproviding a scaffold in and on which tissue may grow. When a patch isused to cover a lesion in the vasculature, such as a vulnerable plaqueor a pre-existing stent, the endothelialization provided by the adhesivemay reduce the risk of plaque rupture, neointimal hyperplasia orrestenosis.

Patches constructed in accordance with the present invention also may beused to deliver one or more therapeutic agents to tissue, as mentionedabove. For example, in some instances a stent may have been placed intoa vessel to provide mechanical support. In these instances, a patch ofthe present invention may be placed within or around the stent todeliver an anti-restenosis agent, which may reduce the risk of in-stentrestenosis and eliminate the need for stent-in-stent implantation.Additionally, the patch of the present invention may promoteendothelialization by delivery of growth factors. In still otherinstances, one or more patches may be used to attach endothelial cellsto the inside of the lumen to promote healing. In yet another proposedapplication, a patch of the present invention may be delivered, e.g.,using a bronchoscope balloon, within a patient's bronchus or trachea todeliver chemotherapy or an anti-cancer drug through the patient'svasculature or tissue.

Although foregoing examples are directed toward intraluminal delivery ofthe inventive patch, it should be noted that patches constructed inaccordance with the present invention may be delivered to any suitableportion of the anatomy. For example, one or more adhesives may bedelivered to one or more hollow body organs, such as the esophagus,stomach, intestines, bronchus, trachea, urethra, ureters, the sinuses,the ears, or the heart. In embodiments configured for use in a heart,the patch may be used to treat or seal a patent foramen ovale, aparavalvular leak, the left auricular appendage, or the like. In otherembodiments, the inventive patches may be used to modify the geometry ofthe left ventricle, and thus reduce functional mitral regurgitation.

Patch Composition

In a preferred embodiment, the patch of the present invention comprisesa mixture of, or separate layers of, a solid fibrinogen component and asolid thrombin component, configured to form a free-standingbiodegradable film or article. When exposed to an aqueous environment,e.g., blood, the fibrinogen and thrombin components undergopolymerization in situ to form a solid fibrin film or article. Thispolymerization models the final stages of the clotting cascade to createa fibrin matrix similar to clots that form naturally in the human body.In accordance with one aspect of the present invention, a suspension offibrinogen is formed using a non-aqueous solvent, such as ethanol. Apredetermined amount of thrombin is dissolved in the non-aqueoussolvent, and mixed with the fibrinogen suspension. The mixture then ispoured into a mold, and the solvent evaporated, leaving a solidfree-standing film or patch comprising unreacted fibrinogen and thrombincomponents. Because, in accordance with the present invention, thefibrinogen and thrombin are combined in a non-aqueous environment, thecomponents do not polymerize to form fibrin until the patch is exposedto an aqueous environment, such as blood.

It is expected that commercially available fibrinogen products may beused to prepare a patch in accordance with the present invention,although commercial fibrinogen products that include excipients orstabilizers, such as sodium citrate or sodium chloride, have beenobserved to provide a relatively inflexible and fragile patch. On theother hand, commercially available purified human fibrinogen productsprepared without any excipients have been observed to produce patches,when made as described herein below, having greater integrity andflexibility. One commercially available fibrinogen product that has beenobserved to provide satisfactory results in initial tests is Part No.PP001S, available from Hyphen Biomed, Neuville-sur-Oise, France,distributed in the United States by Aniara Corporation, Mason, Ohio.This “unsalted” fibrinogen product is used in the Examples describedbelow.

It is expected that commercially available thrombin also may be used toprepare a patch in accordance with the present invention. Initial testsconducted with human thrombin, Part No. AEZ0060, available from HyphenBiomed, Neuville-sur-Oise, France, distributed in the United States byAniara Corporation, Mason, Ohio, have produced satisfactory results. Inaddition, the presence of some excipients in commercial sources ofthrombin have not been observed to effect the mechanical characteristicsof the patch.

Unlike previously-known fibrin coated stents such as those described inthe Dinh patent, wherein fibrinogen and thrombin are reacted in vitro toform stent coatings, in the present invention the fibrinogen andthrombin are polymerized only after being delivered to the targetlocation. When combined in a moist environment, thrombin convertsfibrinogen into fibrin monomers, which are in turn polymerized to formfibers. These fibrin fibers join together into a network structure,resulting in a fibrin matrix. The patch of the present invention mayinclude one or more additional components, such as calcium, Factor XIIIand bovine aprotinin, which may affect the rates of polymerization andbiodegradation. Importantly, because fibrin is a part of the body'snatural clotting mechanism, the in situ formed fibrin patches of thepresent invention are biocompatible, non-thrombogenic, biodegradable,and have a high affinity for various biological surfaces.

As a further alternative, a patch in accordance with the presentinvention may comprise a layer of solid fibrinogen, preferably unsalted,as described above). Such fibrinogen-only or fibrinogen plus calciumsalt patches are expected to have different mechanical properties whendelivered to tissue compared to patches that contain thrombin. Asexplained earlier, however, the addition and amount of calcium salt maybe tailored to obtain specific mechanical properties for a patch, as maybe suitable for particular applications.

The patches of the present invention may be formed as a solid film orpatch using any of a number of deposition techniques, and as describedbelow, may include therapeutic agents or radio-opacifiers. Thefibrinogen and, if present, thrombin components may be deposited on asurface via spray coating, dip coating, brushing, rolling, spinning,inkjet printing, or the like. In some instances, as will be described inmore detail below, a patch may be formed directly onto one or moreportions of one of the delivery systems described here, such as one ormore balloons. In other instances, a patch may be formed on a temporaryprotective layer, which may be removed before, during, or immediatelyprior to delivery of the patch. Preferably, the patch should havesufficient structural integrity so as to be free-standing when removedfrom the delivery system or temporary protective layer.

As noted above, the physical properties of a patch may change during thepolymerization process, after exposure to a moist environment.Generally, as the polymerization process begins (e.g., when thrombin andfibrinogen are combined in the presence of water), the patch maytemporarily become a gel and become highly adherent. Generally, it isexpected that the patch may be freely manipulated, stretched, ordeformed when in its temporary gel form. The duration of the gel stagemay be dependent on the relative and overall concentrations of thefibrinogen and thrombin components, as well as the presence of any othercomponents.

Both the relative and overall concentrations of each of the patchcomponents may affect the rate of fibrin polymerization, as well as thephysical characteristics of the resulting fibrin matrix. For example, ahigher concentration of thrombin in a patch may shorten the settingtime, thereby decreasing the amount of time the patch remains in a gelform. A higher thrombin concentration also is expected to produce asupple fibrin matrix with relatively low load-bearing capabilities.Conversely, a higher concentration of fibrinogen may increase thesetting time for the patch, result in a less porous and stiffer fibrinmatrix, and decrease the degradation rate of the patch. Other patchadditives, such as calcium, Factor XIII, aprotinin, or other additives(e.g., plasticizers, radio-opacifiers, film-forming agents and the like)also may affect the resulting fibrin matrix. As such, the composition ofthe patch may be tailored to achieve a preferred setting time, matrixstiffness, porosity, and degradation rate, depending upon the intendedapplication.

As mentioned above, the patch may include one or more additives that mayaffect the formation of a fibrin matrix. For example, a patch mayinclude Factor XIII, which when activated, forms cross-links betweenfibrin molecule chains that stiffen the fibrin matrix. In othervariations, a patch may include an inorganic calcium salt such ascalcium chloride. Because calcium ions serve as a cofactor in theconversion of fibrinogen to fibrin, the presence of these calcium saltsmay increase the rate of polymerization. Additionally, because calciumions are required for the activation of Factor XIII, their presence mayaffect the extent of cross-linking in the fibrin matrix.

In some embodiments, a patch constructed in accordance with theprinciples of the present invention may comprise one or moreplasticizers that may increase the flexibility of the patch, improvingthe patch integrity and making it less prone to cracking or flaking.Examples of suitable plasticizers include, but are not limited to,phthalate esters (e.g., diethyl phthalate), sebacate esters (e.g.,dibutyl sebacate), citrate esters (e.g., triethyl citrate, tributylcitrate), glycerol derivatives (e.g., propylene glycol, poly(ethyleneglycol)), surfactants, preservatives, combinations thereof, and thelike. The amount of plasticizer may vary depending on the intendedapplication as well as the desired flexibility for the patch, andgenerally will comprise less than about 50% of the constituents used toprepare the patch.

In other embodiments, a patch may comprise one or more radio-opacifiersubstances that allow the patch to be imaged fluoroscopically prior to,during, or after implantation. Examples of suitable radio-opacifiersinclude, but are not limited to, materials containing bismuth, barium(e.g., barium sulphate), gold, iodine, platinum, or tantalum, zirconiumoxide and iron oxide. In some embodiments described below, theradio-opacifier may be provided in high concentrations in only discreteareas of the patch.

The patch of the present invention optionally may incorporate one ormore film-forming agents. Generally, a film-forming agent may assist informing a continuous film during the deposition process, and may includeone or more biodegradable polymers, such as, for example, polycarboxylicacid, polyanhydrides (e.g., maleic anhydride polymers), polyorthoesters,poly-amino acids, poly(carbonate), polyethylene oxide, poly(glutarunicacid), polyphosphazenes, polylactic acid, polyglycolic acid,poly(L-lactic acid), poly(D,L,-lactide), poly(lactide acid-co-glycolicacid), 50/50 (DL-lactide-co-glycolide), polydioxanone, polypropylenefumarate, polydepsipeptides, polycaprolactone,(D,L,-lactide-co-caprolactone), poly-caprolactone co-butylacrylate,polyhydroxybutyrate valerate, polycarbonates (e.g., tyrosine-derivedpolycarbonates and arylates), polyiminocarbonates, cyanoacrylate,calcium phosphates, poluglycosaminogycans, polysaccharides (e.g.,hyaluronic acid, cellulose, and hydroxypropylmethyl cellulose), gelatin,starches, dextrans, alginates, proteins, polypeptides, surface erodiblepolymers (e.g., polyhydroxybutyrate, polycaprolactone, polyanhydrides(both crystalline and amorphous), maleic anhydride copolymers, andzinc-calcium phosphate), copolymers thereof, derivatives thereof,mixtures thereof, and the like.

In accordance with another aspect of the present invention, the patchoptionally may incorporate one or more therapeutic agents intended forlocal or systemic delivery. When a patch is delivered into the body, thetherapeutic agent may be at least temporarily stored in the patch. Insome variations, the therapeutic agent may diffuse out of the patch. Inother variations where the patch is biodegradable, the therapeutic agentmay be released from the patch as the patch biodegrades. The selectionof therapeutic agent or agents, the timing of delivery, and the overallamount of therapeutic agent released from the patch may be determined bythe intended treatment plan, and a specific composition for the patchmay be chosen to achieve this release profile. In variations where thepatch includes one or more additional components (e.g., a plasticizer, afilm-forming agent, etc.), any of the additional components mayincorporate one or more therapeutic agents.

Examples of suitable therapeutic agents include, but are not limited toanti-inflammatory agents, anti-allergenic agents, anti-bacterial agents,anti-viral agents, anticholinergic agents, antihistamines,antithrombotic agents, anti-scarring agents, antiproliferative agents,antihypertensive agents, anti-restenosis agents, healing promotingagents, vitamins, biological molecules such as proteins, genes, growthfactors, cells and DNA, combinations thereof, and the like.

Examples of suitable anti-allergenic agents that may be suitable for usewith the described methods and devices include, but are not limited to,pemirolast potassium (ALAMAST®, Santen, Inc.) and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof. Examples of antiproliferative agents include, butare not limited to, actinomycin D, actinomycin IV, actinomycin II,actinomycin XI, actinomycin C₁, and dactinomycin (COSMEGEN®, Merck &Co., Inc.). Examples of healing promoting agents include, but are notlimited to, sirolimus, everolimus, temsiolimus, and vitamin A.

Examples of antiproliferative agents that may be suitable for use withthe described methods and devices include, but are not limited to,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channelblockers such as nifedipine; colchicines; fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid); histamine antagonists;lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodiesincluding, but not limited to, antibodies specific for Platelet-DerivedGrowth Factor (PDGF) receptors; nitroprusside; phosphodiesteraseinhibitors; prostaglandin inhibitors; suramin; serotonin blockers;steroids; thioprotease inhibitors; PDGF antagonists including, but notlimited to, triazolopyrimidine; and nitric oxide, and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Examples of anti-bacterial agents that may be suitable for use with thedescribed methods and devices include, but are not limited to,aminoglycosides, amphenicols, ansamycins, β-lactams such as penicillins,lincosamides, macrolides, nitrofurans, quinolones, sulfonamides,sulfones, tetracyclines, vancomycin, and any derivatives or combinationsthereof. Examples of penicillins that may be suitable for use with thedescribed methods and devices include, but are not limited to,amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin,aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinicacid, benzylpenicillin sodium, carbenicillin, carindacillin,clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin,methicillin sodium, mezlocillin, nafcillin sodium, oxacillin,penamecillin, penethamate hydriodide, penicillin G benethamine,penicillin G benzathine, penicillin G benzhydrylamine, penicillin Gcalcium, penicillin G hydrabamine, penicillin G potassium, penicillin Gprocaine, penicillin N, penicillin 0, penicillin V, penicillin Vbenzathine, penicillin V hydrabamine, penimepicycline, phenethicillinpotassium, piperacillin, pivampicillin, propicillin, quinacillin,sulbenicillin, sultamicillin, talampicillin, temocillin, andticarcillin.

Examples of anti-viral agents suitable for use with the describedmethods and devices include, but are not limited to, acyclovir,famciclovir, valacyclovir, edoxudine, ganciclovir, foscamet, cidovir(vistide), vitrasert, formivirsen, HPMPA(9-(3-hydroxy-2phosphonomethoxypropyl)adenine), PMEA(9-(2-phosphonomethoxyethyl)adenine), HPMPG(9(3-Hydroxy-2-(Phosphonomet- -hoxy)propyl)guanine), PMEG(9-[2-(phosphonomethoxy)ethyl]guanine), HPMPC(1-(2-phosphonomethoxy-3-hydroxypropyl)cytosine), ribavirin, EICAR(5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamine), pyrazofurin(3-[beta-D-ribofuranosyl]-4-hydroxypyrazole-5-carboxamine),3-Deazaguanine, GR92938X(1-beta-D-ribofuranosylpyrazole-3,4-dicarboxami- -de), LY253963(1,3,4-thiadiazol-2-ylcyanamide), RD3-0028(1,4-dihydro-2,3-Benzodithiin), CL387626(4,4′-bis[4,6-d][3-aminophenylN--,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazin-2-ylamino-biphenyl--2-,2′-disulfonicacid disodium salt), BABIM (Bis[5-Amidino-2-benzimidazoly-1]-methane),NIH351, and combinations thereof.

Anti-inflammatory agents may include steroidal and nonsteroidalanti-inflammatory agents. Examples of suitable steroidalanti-inflammatory agents include, but are not limited to, 21acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, any of their derivatives, and combinations thereof.

Examples of suitable nonsteroidal anti-inflammatory agents include, butare not limited to, COX inhibitors. These COX inhibitors may includeCOX-1 or COX nonspecific inhibitors such as, for example, salicylic acidderivatives, aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine;para-aminophenol derivatives such as acetaminophen; indole and indeneacetic acids such as indomethacin and sulindac; heteroaryl acetic acidssuch as tolmetin, diclofenac and ketorolac; arylpropionic acids such asibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin;anthranilic acids (fenamates) such as mefenamic acid and meloxicam;enolic acids such as the oxicams (piroxicam, meloxicam) and alkanonessuch as nabumetone. The COX inhibitors may also include selective COX-2inhibitors such as, for example, diaryl-substituted furanones such asrofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole aceticacids such as etodolac and sulfonanilides such as nimesulide).

Examples of suitable biomolecules include, but are not limited to,peptides, polypeptides and proteins; oligonucleotides; nucleic acidssuch as double or single standard DNA (including naked and eDNA), RNA,antisense nucleic acids such as antisense DNA and RNA, small interferingRNA (siRNA), and ribozymes, genes, carbohydrates. Nucleic acids may beincorporated into one or more vectors (including viral vectors),plasmids, liposomes, or the like.

Examples of suitable proteins include, hut are not limited to serca-2protein, monocyte chemoattractant proteins (“MCP-1”) and bonemorphogenic proteins (“BMPs”), such as, for example. BMP-2 (OP-1),BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. These BMPs may be provided ashomodimers, heterodimers, or combinations thereof. In some variations,molecules capable of inducing an upstream or downstream effect of a BMPmay be provided. This may include, for example, one or more “hedgehog”proteins, or the DNA encoding them. Examples of suitable genes include,but are not limited to survival genes that protect against cell death(e.g., anti-apoptotic Bcl-2 family factors and Akt kinase); SERCA 2gene; and combinations thereof. In some variations, one or moretherapeutic agents may comprise one or more angiogenic factors, such asacidic and basic fibroblast growth factors, vascular endothelial growthfactor, epidermal growth factor, vascular endothelial growth factor,epidermal growth factor, transforming growth factor and,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor, hepatocyte growth factor, and insulinlike growth factor. In some variations, a therapeutic agent may compriseone or more cell cycle inhibitors (e.g., a cathepsin D (CD) inhibitor).Examples of suitable anti-restenosis agents include, but are not limitedto, Rb, nFkB and E2F decoys, thymidine kinase (“TK”), combinationsthereof, and the like.

Examples of suitable small molecules include, but are not limited to,hormones, nucleotides, amino acids, sugars, and lipids and compoundshave a molecular weight of less than 100 kD. Examples of suitable cellsinclude, but are not limited to, stem cells, progenitor cells,endothelial cells, adult cardiomyocytes, smooth muscle cells, sidepopulation (SP) cells, lineage negative (Lin−) cells (e.g., Lin−CD 34−,Lin−CD34+, Lin−cKit+, and the like), mesenchymal stem cells includingmesenchymal stem cells with 5-aza, cord blood cells, cardiac or othertissue derived stem cells, whole bone marrow, bone marrow mononuclearcells, whole bone marrow, bone marrow mononuclear cells, endothelialprogenitor cells, skeletal myoblasts or satellite cells, muscle derivedcells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts,smooth muscle cells, adult cardiac fibro blasts +5-aza, geneticallymodified cells, tissue engineered grafts, MyoD scar fibroblasts, pacingcells, embryonic stem cell clones, embryonic stem cells, fatal orneonatal cells, immunologically masked cells and teratoma derived cells.Cells may be of human origin (autologous or allogenic), of animal origin(xenogenic), or may be genetically engineered. Any of the foregoingdrugs or biologically active molecules may be encapsulated, for example,in microparticles or liposomes, prior to incorporation within the patch.

Other bioactive agents useful in the present invention include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; everolimus; tacrolimus;40-O-(3-hydroxyl)propyl-rapamycin;40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs; estradiol; clobetasol; idoxifen; tazarotene;alpha-interferon; host cells including, but not limited to prokaryotesand eukaryotes such as, for example, epithelial cells and geneticallyengineered epithelial cells; dexamethasone; and, any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Patch Configurations

Patches constructed in accordance with the principles of the presentinvention may be manufactured in either an adherent or non-adherentstate. Alternatively, a patch may be manufactured in a non-adherentstate, and activated prior to use, for example, by dipping in warm waterprior to application or delivery to the body. As yet anotheralternative, the patch may include a water-soluble protective coating,for example, for intravascular applications, to prevent the fibrinpolymerization process from beginning before the patch is delivered to atarget location.

Referring now to FIG. 1, a first embodiment of a patch constructed inaccordance with the principles of the present invention is described.Patch 100 comprises free-standing single layer 102 formed from a mixtureof unreacted fibrinogen 104 and thrombin 106, prepared as discussedabove. Patch 100 may include one or more additional components oragents, such as those described above. As a further alternative,thrombin 106 may be omitted entirely. Preferably, patch 100 has athickness in a range of 50 μm-200 μm, and more preferably 30 μm-500 μm,sufficient to provide a free-standing article. Alternatively, layer 102may be built-up by deposition of several thinner films. In one preferredembodiment, the ratio of thrombin is about 0 to 1 NIH per mg offibrinogen and the ratio of inorganic calcium salt (e.g., CaCl₂) is 0 to5 mg per mg of fibrinogen. In addition, patch 100 preferably includes aplasticizer, such as polyethylene glycol, in a ratio from 0 to 0.5 mgper mg of fibrinogen. A therapeutic agent, if present, may be multiplesof the patch weight, for example, about 0 to 10 mg therapeutic agent permg of fibrinogen. For slow release therapeutic applications, however,applicant expects a ratio of about 0 to 1 mg therapeutic agent per mg offibrinogen to be more suitable.

FIG. 2 illustrates an alternative embodiment the present invention, inwhich patch 200 comprises separate sublayers of unreacted fibrinogencomponent and thrombin component. In particular, patch 200 comprisesfibrinogen sub-layer 204 and thrombin sub-layer 206. In some alternativeembodiments, sub-layer 206 may be omitted entirely, the thrombin topolymerize the fibrinogen may be supplied by the environment in situ. Inother embodiments, fibrinogen sub-layer 204 and thrombin sub-layer 206may be separated by a water-soluble protective layer. In somevariations, the protective layer may at least temporarily protect thesublayers from certain substances or stimuli prior to or duringdelivery, for example, exposure to moisture, to prevent prematureactivation. Alternatively, the protective layer may be selectivelyremoved to control the activation of the patch. In embodiments in whichthe patch is already in an adherent form, a protective layer may helpprevent premature adhesion between the patch and surrounding tissue. Inother instances, the protective layer may protect the patch frommechanical damage prior to or during delivery. In still otherembodiments, a protective layer may allow a patch to be folded withoutadhering to itself. In yet other embodiments, a protective layer may beused to at least temporarily join a patch to a delivery system, asdescribed below.

In some embodiments, a protective layer may be removed from the patchprior to or during delivery of the patch. In this way, a patch may beconfigured such that only the fibrin-forming layers (as well as anadditives or therapeutic agents) are delivered to tissue. The protectivelayer may be made from a water-soluble material, a material that issoluble in another media, a material that is electrolyticallydecomposable, a bioerodable or biodegradable material, combinationsthereof, or the like. Examples of suitable water-soluble materialsinclude, but are not limited to, polysaccharides (e.g., hyaluronic acid,cellulose, hydroxypropylmethyl cellulose, gelatin, starches, dextrans,alginates, their derivatives, and the like), contrast agents (e.g.,diatrizoate, metrizoate, ioxaglate, iopamidol, iohexol, ioxilan,iopromide, iodixanol, and the like), sugar-based polymers (e.g.,sucrose), water-soluble hydrogels, combinations thereof, and the like.

In FIG. 3, patch 300 is described that includes fibrin-forming layer 302and protective layers 304. While patch 300 is depicted in FIG. 3 ashaving protective layer 304 on both sides of layer 302, the patch mayinclude only one protective layer 304 attached thereto. In still otherembodiments, patch 300 may comprise a single layer 302 of a mixture ofunreacted fibrinogen and thrombin, which protective layer 304 covers allof the exposed surfaces of the patch. While shown in FIG. 3 as havingsingle layer 302 of unreacted fibrinogen and thrombin (similar to thatdescribed with respect to FIG. 1), patch 300 may comprise any number offibrin-forming layers 302, each of which may include differentformulations. e.g., different ratios of thrombin to fibrinogen, ordifferent amounts of plasticizer, as required for a particularapplication. Such construction may provide layers having differentsetting or degradation times, different stiffness, or release differentdrugs. As such, multiple adhesive layers may provide a user withadditional flexibility in creating a patch in accordance with thepresent invention.

Referring to FIG. 4, a further alternative of a patch constructed inaccordance with the principles of the invention is described. Patch 400comprises discrete or interconnected portions or strands 402 of solidunreacted fibrinogen and thrombin disposed within matrix 404. Matrix 404may be a water-soluble material, such as those described above, or maybe made from a biodegradable or bioerodible material, such as thebiodegradable polymers described above. In some of these variations,matrix 404 may protect the fibrin-forming components 402 from prematureactivation. Additionally, matrix 404 may provide patch 400 withadditional flexibility or rigidity, as may be desired for a particularapplication.

When patch 400 is delivered, e.g., through the vasculature of a patient,the solid unreacted fibrinogen and thrombin portions 402 may adhere totissue. However, matrix 404, which may be a water-soluble material,initially protects the fibrin-forming components from polymerizing. Aswater-soluble matrix 404 dissolves during exposure within the body,portions 402 are exposed, thereby initiating polymerization. Suchexposure also may allow the fibrin gel to adhere to the bodily tissueand cure to form a fibrin-matrix patch. Pressure applied by a deliverydevice (e.g., by an inflated balloon), may cause portions 402 to joinand form a continuous film within the body. In other embodiments, matrix404 may be a biodegradable material, such that exposed portions of theunreacted fibrin-forming components 402 become adherent, therebyallowing patch 400, including biodegradable matrix 404, to adhere tosurrounding tissue.

In other variations, a patch of the present invention may be formed withthe unreacted fibrinogen and thrombin components, or just a fibrinogencomponent, arranged in predetermined patterns. For example, in somevariations, the fibrin-forming components may be arranged in a mesh-likepattern. In still other variations, the fibrin-forming components may bedivided into a plurality of discrete segments. FIGS. 5A-5D illustrateone such variation, patch 500. FIG. 5A is a perspective view of patch500, which includes protective layer 502 and fibrin-forming segments 504deposited on protective layer 502. While shown in FIG. 5A as havingprotective layer 502, it should be appreciated that fibrin-formingsegments 504 alternatively may be deposited directly onto one or moreportions of a delivery device, with or without a protective layer. Anadditional protective layer (not shown) may be used to cover some or allof the fibrin-forming segments during delivery.

As illustrated in FIGS. 5B through 5D, although fibrin-forming segments504 may be divided into a number of discrete segments, some or all ofthe segments 504 may be joined in situ to form a continuous film. Morespecifically, in embodiments in which segments 504 take on a gel formafter activation, the segments may be manipulated or remodeled by theapplication of one or more forces. For example, when patch 500 describedabove is pressed against vessel wall 506 by an expandable deliverydevice (not shown), the device and vessel wall may apply pressure(indicated by the arrows in FIG. 5B) to segments 504 that cause thegelatinous, partially-cured fibrin-forming segments 504 to deformoutwardly, as shown by arrows 510. This deformation may in turn causeindividual segments 504 to join into solid fibrin film 512, as depictedin FIG. 5C. Protective layer 502 may thereafter be removed or dissolve,such that fibrin-forming segments 504 completer the process ofpolymerizing to form fibrin matrix 514, as shown in FIG. 5D.

Dividing the unreacted fibrinogen and thrombin components into discretesegments 504 may provide a number of advantages. For example, a patchmade up of discrete segments 504 may have additional flexibilitycompared to a solid continuous layer, thereby enabling the patch to befolded to facilitate transluminal delivery. In other instances, discretesegments 504 may be used to form a continuous patch that will not blocka side branch when deployed in a branched blood vessel. In such cases,it is expected that only those segments 504 that contact a tissuesurface will deform, and thus segments 504 that do not contact tissuewill not contribute to forming a continuous film. As such, if a ballooncarrying discrete segments 504 is expanded inside of a branched vessel,those segments that are expanded toward the side branch will not contacttissue, and thus will not become part of the resulting patch.

A patch of the present invention may have any suitable size and shape,such that the dimensions of the patch may be determined at least in partby the dimensions of the anatomy in which the patch will be applied. Inaddition, solid patches of unreacted fibrinogen or thrombin, with orwithout additional additives as described above, may be modeled into anysuitable size of shape, depending upon the intended application. FIGS.6A-6E illustrate a number of patches and articles modeled from suchpatches. For example, FIG. 6A illustrates patch 600 having the form of ahollow cylinder, and may find particular utility where the patch will beplaced in a cylindrical hollow body organ. Patch 602 of FIG. Billustrates that a patch of the present invention may take on any otherthree-dimensional shape, such as a frustoconical section.

Other suitable three dimensional shapes may include, but are not limitedto spheres, hemispheres and cones. In FIG. 6C, patch 604 is configuredas a branched cylinder having main trunk 606 and first 608 and second610 side branches, such as may be required to provide internal orexternal support for a branched vessel. While shown in FIG. 6C as havinga generally y-shaped configuration, patch 604 may be configured suchthat side branches 608 and 610 project from main trunk 606 at anydesired point along the length of main trunk 606.

In other embodiments, a patch constructed in accordance with theprinciples of the present invention may be formed in a flat shape, suchas patch 612 of FIG. 6D. While shown in FIG. 6D as being approximatelyrectangular in shape, patch 612 may be any suitable shape, including,but not limited to, a circle, an oval, a triangle, a square, anotherpolygon, or a shape with irregular geometry. Additionally, patch 612 maybe rolled, folded, bent or otherwise modified to form athree-dimensional shape. For example, FIG. 6E shows rectangular patch614 that has been curved to form a half-cylinder, e.g., to mate with aninterior surface of a vessel to occlude or isolate an aneurysm. In othervariations, the shape of the patch may be dependent on the system thatwill deliver it. For example, a patch according to the present inventionmay be formed by depositing a film of unreacted fibrinogen and thrombin,or just unreacted fibrinogen, without or without a salt component, on aportion of the delivery system (e.g., a balloon). In such instances, theshape of the patch will be the same or similar to the shape of deliverysystem.

It should be appreciated that the shape and dimensions of a patch maychange before or during delivery of the patch. For example, the patchmay be folded, crimped, stretched or otherwise deformed in a manner thatmodifies, temporarily or permanently, the shape of the patch.Furthermore, the ultimate size and shape of the in situ patch formedwithin the body may differ from the shape of the patch as manufactured.Due to the deformability of the fibrinogen and thrombin componentsduring polymerization, some patches may be molded or otherwise deformedduring delivery. For example, in variations where a cylindrical patch isdelivered using a balloon, inflation of the balloon may cause the patchto expand to a larger radius.

Delivery Systems and Methods

The patches described herein may be delivered using of a number ofpreviously-known delivery systems, which may comprise one or moreexpandable members, such as a balloon or expanding mandrel or cage. Inembodiments that include an expandable member, the expandable member maybe expanded at the delivery site to position a patch so that it is inapposition with tissue. In instances where a patch is placed in a dryenvironment, or when the delivery system is used to deliver a liquidcomponent, the delivery system may additionally include one or morelines, lumens, ports or the like for delivering water or a liquidcomponent to activate the patch.

In instances where the patch is delivered using a balloon catheter, theballoon may be compliant, semi-compliant, or non-compliant.Non-compliant balloons are relatively inelastic, and the balloonmaterial does not stretch significantly when the balloon is inflated. Assuch, a deflated non-compliant balloon usually will have excess materialthat is folded or rolled to place the balloon in a low-profileconfiguration. Conversely, compliant balloons are relatively elastic,and thus the material tends to stretch and expand when the balloon isinflated. A deflated non-compliant balloon may not have an excess ofballoon material, and thus may not need to be folded or rolled.Semi-compliant balloons tend to have an intermediate level of elasticityand upon inflation stretch and expand to a lesser degree than compliantballoons would under similar circumstances. Semi-compliant balloons mayor may not need to be rolled or folded.

When a balloon catheter is used to deliver a patch of the presentinvention, the patch may first be placed on or otherwise attached to theballoon. In some variations, a patch may be mechanically attached to theballoon. Alternatively, one or more clips, sutures, coatings or othermechanical structures may be used to hold the patch to the balloon. Invariations where a non- or semi-compliant balloon is either folded orrolled, the folding or rolling of the balloon may hold the patch againstor to the balloon. FIGS. 7A and 7B illustrate one manner by which apatch may be folded with a non-compliant or semi-compliant balloon tomechanically hold the patch on the balloon. In particular, FIG. 7Adepicts cylindrical patch 700 and balloon catheter 702 comprisingballoon 704. As shown in FIG. 7A, balloon 704 has been placed inside ofthe patch 700 and inflated. To hold patch 700, balloon 704 may bedeflated and folded. During this process, patch 700 becomes folded alongwith the non-compliant balloon, as shown in FIG. 7B, such that theresulting folds of balloon 704 temporarily hold patch 700 on theballoon. Patch 700 is released when balloon 704 is later re-inflated.

In other embodiments, the patch may be temporarily attached to theballoon using one or more adhesives, which may be water-soluble andrelease the patch when exposed to water. For example, in some variationsa water-soluble protective layer may be used to join a patch to adelivery system and later release the patch from the delivery system. Inother variations, the adhesive may lose its grip on the balloon inresponse to one or more stimuli (e.g., heat, energy, electricity) whichmay be applied to the balloon catheter to release the patch in situ.

In still other embodiments, the unreacted fibrinogen and/or thrombincomponents of the patch may be deposited directly onto the balloon of adelivery catheter using any suitable deposition process. Examples ofsuitable deposition methods include, but are not limited to, spraycoating, dip coating, brushing, rolling, spinning, inkjet printing,casting or the like. Where the patch comprises multiple layers (e.g.,protective layers and adhesive layers), each layer may be appliedsequentially, and may be applied using the same or different depositionmethods. For example, a balloon may first be coated with a protectivelayer, a layer of unreacted fibrinogen and thrombin then applied, andfinally the assembly may be coated with an additional protective layer,such as a water-soluble layer. When multiple discrete segments are usedto create the patch, such as described with respect to patch 500 of FIG.SA, segments 504 may be applied simultaneously or sequentially.Additionally, the final layer of protective coating also may serve tosecure the patch to the balloon.

When the fibrin-forming components are used to at least partially coat aballoon, the balloon may be either deflated or inflated when coated. Forexample, in some variations an inflated non-compliant or semicompliantballoon may be coated with a patch, deflated, and then rolled or foldedwith the solid patch attached thereto. In other instances, a deflatednon-compliant or semicompliant balloon may be rolled or folded, and thencoated with a patch. Compliant balloons may be coated when they are atleast partially deflated. Additionally, the balloon of a ballooncatheter may be made from or coated with a non-stick material, such asPTFE. In this case, the non-stick material may help to prevent the patchfrom adhering to the balloon during patch activation and delivery. Theballoon of the delivery catheter optionally may be textured, dimpled, orotherwise patterned to allow for temporary mechanical adherence betweenthe balloon and the patch.

Referring now to FIGS. 8A and 8B, an alternative delivery systemsuitable for delivering a patch of the present invention is described.Balloon catheter 800 includes curved, rectangular balloon 802 thatapproximates a cylindrical shape when inflated. When deflated, balloon802 may be folded or rolled into a spiral, as shown in a FIG. 8B.Because balloon 802 may be laid flat when deflated, balloon catheter 800may find particular utility in instances where a patch (not shown) isdeposited directly on balloon 802, for example, by casting, spraying orusing an inkjet printing method. Additionally, because balloon 802approximates a cylindrical shape when inflated, blood may still passthrough lumen 804 defined by balloon 802 during deployment, therebyreducing the risk of upstream ischemia during placement of the patch.

Delivery systems suitable for delivering the patch of the presentinvention may additionally comprise one or more protective sheaths.Generally, an expandable member may be placed in a low-profileconfiguration inside of a sheath, and advanced to a target site. At thetarget site, the sheath may be withdrawn (or the expandable memberadvanced) to reveal the expandable member. In this way, the sheath mayhelp to shield the patch from exposure to moisture or other stimuli asthe patch is advanced through the body. One such delivery system isdepicted in FIGS. 9A-9E. Alternatively, the sheath may have a diameterthat varies along the length of the catheter, e.g., having a smallerdiameter on the shaft and an enlarged diameter in the vicinity of theballoon, so that the sheath does not reduce flexibility of the deliverysystem.

In FIGS. 9A to 9E, delivery system 900 comprises sheath 902, collar 904disposed on sheath 902, and shaft 906 with cap 908. Cap 908 may beconfigured to engage the distal end of sheath 902 to seal the interiorof sheath 902 from the external environment during advancement of thedelivery system through a patient's vasculature. Shaft 906 may beslidable relative to sheath 902 to move cap 908. To deliver a patchwithin vessel V, guidewire 912 is first advanced to a target site, asshown in FIG. 9B. Sheath 902 then is advanced along guidewire 912 viacollar 904, as depicted in FIG. 9C. While shown in FIGS. 9A-9E as havinga collar, delivery system 900 need not include such structure, butinstead may employ any other structure used for advancing a catheter.Once sheath 902 has been advanced to the target site, shaft 906 isadvanced relative to sheath 902 to expose balloon 914 (or anotherexpandable member), as shown in FIG. 9D. Balloon 914 then is expanded tobring the patch (not shown) into apposition with the interior of vesselV. Balloon 914 may be retained in position for a sufficient period oftime for the patch to activate and adhere to the vessel wall, e.g., 30seconds to several minutes. Balloon 914 then is deflated and deliverysystem 900 removed.

In accordance with another aspect of the present invention, methods areprovided for delivering one or more fibrin-matrix forming patches to abody. The patches may be delivered to any suitable portion of theanatomy, including the interior of a blood vessel, and may providelocalized or systemic delivery of one or more biological molecules ortherapeutic agents. In some applications, the patches may be used toseal a puncture, tear, or dissection in a blood vessel. In otherapplications, the patches may be used to support a vessel, such as avessel weakened by aneurysm, or to occlude or isolate an aneurysm orfistula. In still other applications, one or more patches may be used tosupport or reline a stent disposed within a blood vessel, or to supportor seal a vulnerable plaque. The patches of the present invention alsomay be delivered to the heart, for example, to close a patent foramenovale, a paravalvular leak, the left auricular appendage, or to modifythe geometry of the left ventricle.

As described above, the patch of the present invention may be deliveredusing any suitable delivery system, such as those described above. Thedelivery system may comprise a sheath, which may or may not besteerable. Advancement of the delivery system and deployment of thepatch may occur under direct visualization, indirect visualization, or acombination thereof. In variations where the delivery system is advancedusing indirect visualization, any suitable visualization technique maybe used (i.e., fluoroscopy, ultrasound), and either the delivery systemor the adhesive may include one or more radiographic components to helpaid in visualization.

Once the patch has been advanced to the target location, it may bepositioned such that it is in contact with bodily tissues. The deliverysystem preferably places the patch in contact with bodily tissue such asby expanding an expandable member (e.g. a balloon). In some instances,the expansion of a balloon or other expandable member causes the patchto stretch or deform when in a gel state. The delivery system maycontinue to hold the patch in contact with the bodily tissue in astretched or deformed state until the fibrin matrix cures, so as to notdiminish the strength of the patch during curing.

The patch may be manufactured in a non-adherent form, and activated atany time prior to or during delivery. Generally, this occurs when thepatch is exposed to a moist environment. In some applications, a usermay activate a patch prior to introducing the patch into the body.Assuming the setting time for the patch is known, a user may monitor thetime remaining before the in situ patch sets. Such embodiments mayadditionally benefit from a patch composition having a longer settingtime (e.g., greater than five minutes), thereby enabling the patch to beadvanced to and placed at a target location.

As discussed above, activation of the unreacted fibrinogen and thrombincomponents may be controlled by the presence of one or more protectivelayers. In these embodiments, one or more protective layers may protectthe patch from activating substances or stimuli. Once the protectivelayers are removed or dissolve, the fibrin-forming components beginpolymerizing. For example, in variations where the patch is covered by awater-soluble protective layer or is impregnated in a water-solublematrix, the layer or matrix may be configured to dissolve over apredefined period of time when introduced into an aqueous environment.In this way, fibrin polymerization will begin a predetermined intervalafter introduction into an aqueous environment. In other applications, auser may initiate polymerization by selective removal of a protectivelayer or applying an activating substance to the patch.

In yet other methods, as described above, the delivery system maycontrol adhesive activation. For example, the patch may be delivered viaone or more scaled sheaths, such that activation may be selectivelyinitiated by unsealing the sheath and allowing the patch to be exposedto one or more activating substances or stimuli in the surroundingenvironment. In other embodiments, the delivery system may be configuredto introduce a liquid component to activate the patch prior todeployment, e.g., by flushing a fluid through the interior of the sealedsheath to activate the patch prior to deploying the patch from thesheath.

In embodiments where a delivery system is used to introduce theinventive patch to a target location, the delivery system may be removedat any suitable time. In some applications, the delivery system may beremoved once the patch has been placed in contact with bodily tissue,but before it has fully set. In other applications, the delivery systemmay be retained in position until the patch has fully set. Placement ofpatch may be confirmed via direct or indirect visualization prior toremoval of the delivery device.

EXAMPLES

A patch in accordance with the principles of the present invention wasprepared using commercially available fibrinogen, thrombin and calciumchloride. It was observed that the type, amount and ratio of thesecomponents significantly affects the properties of the patch, includingflexibility, microstructure, and adhesive strength. As discussed inlater examples, it was found that the addition of additives rendered thepatch more flexible.

Example 1

Fibrinogen powder was prepared by grinding 25 mg of commerciallyavailable fibrinogen and suspending it in 1 ml of ethanol. 10 NIH ofcommercially available thrombin was first dissolved in 2 ml of water.4.4 mg of CaCl₂ was dissolved in 1 ml of ethanol. 160 μl of thrombinsolution was added to the CaCl₂ solution and mixed. The resultingmixture was added to the fibrinogen suspension, mixed, and then pouredinto a circular mold having a surface area of 10 cm². The mold wasplaced under 30 mm Hg vacuum for three hours to evaporate the ethanoland water. A free-standing patch was formed having sufficient strengthto be removed from the mold. The patch, when exposed to saline, becameelastic and adhesive.

The strength of the patch in its dry state is important, as the patchmust have sufficient structural integrity to be free-standing, and yetretain sufficient flexibility to be configured for delivery via adelivery system, e.g., wrapped around a balloon and tightly folded.Several parameters were observed to effect the strength and flexibilityof the patch, including:

-   -   The components: Fibrinogen may be prepared in different forms        and by various methods. It was observed from experimenting with        different sources of fibrinogen that an un-salted preparation of        fibrinogen may produce the most desirable results. The presence        of salts (usually added during lyophilization of fibrinogen and        for stability purposes) can render the resulting patch very        brittle. Likewise, it was observed that preparations of pure        thrombin provided greater flexibility of the patch.    -   Additives: Various types of plasticizers were investigated as        potential additives, including PEG-6000. PEG-3000, PEG-1500,        PEG-400, glycerol, and polyvinyl pyrrolidone (PVP) in different        percentages. It was observed that 5-30 wt % of PEG-400 added to        the patch preparation produced desirable results.    -   Storage conditions: It was observed that after the patches were        dried in vacuum and the ethanol removed, storing the patches in        humid environment significantly improved the flexibility of the        patches. Preliminary testing showed a relative humidity of        40-60% provided acceptable results. Such storage conditions were        maintained for patches later wrapped around the balloons of        delivery systems, as described in later Examples.

Example 2

25 mg of unsalted fibrinogen was suspended in 1 ml ethanol and 100 μl ofa 100 mg/ml solution of PEG-400 was added to the fibrinogen suspension.A thrombin solution containing CaCl₂ was prepared as in Example 1 andmixed with the suspension of fibrinogen and PEG-400. The resultingmixture was mixed and poured into a circular mold having a surface areaof 10 cm² and then placed under 30 mm Hg vacuum for three hours to dry.The patch was measured to have a thickness of about 150 μm, and wasstored in an environment with 60% humidity.

Example 3

A delivery system suitable for delivering a patch as described in thepreceding examples was prepared including a standard angioplastycatheter onto which a water soluble coating was applied to ensurerelease of the patch from the balloon. A water soluble coating of eitherPEG-6000 or Polyvinylpyrrolidone (PVP) dissolved in ethanol has beendetermined to be particularly useful. When initially sprayed onto aballoon, solutions of PEG-6000 and PVP become adherent in highconcentrations, however, the stickiness disappears as the solution driesinto a film. The water soluble coating has been observed to serve tworoles: (i) it acts as a temporary glue to adhere the patch to thedelivery system; and (ii) during delivery and when immersed in saline orbody liquids, the coating dissolves and releases the patch from thedelivery system.

A patch made in accordance with the present invention can be wrappedaround the balloon of a balloon catheter in several ways. In a firstmethod, the balloon is totally inflated, sprayed first with a watersoluble coating, and then the patch wrapped around the balloon while thewater soluble coating is still wet; the balloon then is deflated, dried,and folded. In a second method, the balloon is totally deflated, and maybe held under negative pressure (such as applied by a syringe). In thissecond method, the balloon is sprayed with a water soluble coating, thepatch is wrapped around the balloon, and the assembly then is dried andfolded. In yet a third method, the balloon is partially inflated andsprayed with a water soluble coating; after which the patch is applied,the balloon is deflated, and the assembly dried.

A water soluble coating of 50 mg/ml of PVP in ethanol was prepared. A10×40 mm angioplasty balloon was inflated to 4 atm pressure and sprayedwith the PVP solution in ethanol. Before the PVP solution dried, a patchprepared as in example 2 above was wrapped around the balloon. Theballoon then was deflated and dried. In a second test, a commercial 6×40mm balloon was unwrapped (from its tight fold) and sprayed with a watersoluble coating. A patch prepared as in Example 2 was wrapped around theballoon, and the assembly was dried and folded back again into a tightfold. Alternatively, the patch and balloon may be tightly folded andthen dried.

Example 4

Use of a sheath on the exterior of the patch and balloon catheter wasinvestigated to reduce fluid uptake and premature activation of thepatch. It is believed to be important that the sheath be sufficientlyclose fitting to prevent water from penetrating the gap between thepatch and the sheath, so as to prevent the patch from becoming activatedprematurely and adhering to the sheath. On the other hand, sliding atightly fitting sheath over the patch could potentially mechanicallydamage the patch. In addition, other methods may be employed to preventwater from entering the sheath during delivery, such as by providingpillows on the balloon that permit it to be partially inflated to sealthe gap between the balloon catheter and sheath.

A patch prepared as described in Example 2 was wrapped around a 10×40 mmballoon prepared as described in Example 3. A sheath having an innerdiameter of about 2.5 mm was easily slid over the patch and the balloonso the patch was not damaged. The balloon was then inflated inside ofthe sheath to about 2 atm pressure to achieve a tight seal between theballoon and the sheath. During delivery, after the balloon is disposedat the deployment site, negative pressure may be applied to the balloonand the sheath slid away. The balloon may then be inflated to deploy thepatch.

Example 5

The effect of the balloon size on patch delivery was investigated. Itwas observed that the ratio of balloon diameter to target lumen diameterplays an important role in successful deployment of the patch. Inparticular, it was observed that the target lumen needs to besufficiently large enough so the balloon can travel inside it easily,and without significant friction. The lumen also must be sufficientlylarge that, after the patch is deployed and the balloon is deflated, thepatch is not mechanically damaged, e.g., scratched off, when the balloonis being removed. As a further consideration, the artery or lumen mustbe sufficiently small that inflation of the balloon inside of the lumencreates enough pressure against the luminal wall that the balloon comesfully in contact with the luminal wall over its entire area. It wasobserved that a ratio of balloon diameter to target lumen diameter ofabout 1.1:1 provided good results. Accordingly, a 10 mm balloon isbelieved to be suitable to deliver a patch inside a 9 mm lumen. Inaddition, folding of the balloon and ratio of the deflated to inflatedsize of the balloon can impact the results obtained: it was generallyfound desirable to have the balloon folded to the smallest diameterattainable without damaging the patch.

A patch wrapped around a 10×40 mm balloon as prepared in Example 3 wasexpanded inside a plastic tube with an inner diameter of about 9 mm,while the plastic tube was immersed in saline solution. In order todeploy the patch, the balloon was expanded to 8 atm and held at thatpressure for 10 seconds before being deflated and removed. In a separatetest, a similar tube with a patch deployed inside, as described above,was placed in a flow system with a flow rate of about 1200 ml/min. Thepatch remained intact for the 48 hour duration of the experiment. Bycomparison, the flow rate in human superficial femoral artery, apotential target site for deployment of the inventive patch, is about200 ml/min. Similar tests conducted with beef aorta instead of plastictubing produced comparable results for patch deployment and durability.

Example 6

Feasibility of use of a patch in accordance with the present inventionin a lumen having a side branch was investigated. As discussed above, itis contemplated that a patch constructed in accordance with the presentinvention could be deployed in a vessel having a side branch, withoutoccluding the side branch. In particular, it is believed that a patchdisposed within a target vessel adheres to only those portions of thevessel wall where the patch was brought into apposition by the deliverysystem. Preferably, the area of the patch facing the side branch openingwould remain on the balloon, thus leaving the side branch open.

A patch and delivery system as described in Example 3 was prepared, andthe patch was deployed inside a plastic tube having a 3 mm diameter holedrilled on one side of the tube to represent a side branch. Afterdeployment of the patch, the side branch remained open and a 9 mm² areaof the patch was found to have remained on the balloon, corresponding tothat portion of the patch that was deployed against the hole.

Example 7

The feasibility of using a patch of the present invention for drugdelivery was investigated. The expectation that it is possible toincorporate any therapeutically useful molecule or ingredient in theformulation of the patch as described herein was tested using patchincluding PEG-400 and a dye. It is contemplated that therapeutic agentscan be incorporated in the formulation in a similar fashion. Forexample, a desired therapeutic molecule may be dissolved or suspended inan organic solvent and added to either the fibrinogen or the thrombinsolutions during the preparation of the patch. In this way the moleculewill be trapped inside the fibrin structure and will be delivered overtime as the fibrin biodegrades.

Red dye was ground and suspended in ethanol in a ratio of 100 mg/ml. Apatch was prepared using the formulation of Example 2, except that 40 μlof the color suspension was added to the fibrinogen suspension prior tomixing with the thrombin solution. After drying, the patch was placed in4 ml of saline solution and monitored at 2 hour intervals. After 4hours, it was observed that the red dye had been slowly released intothe saline solution. Similar release is expected to occur with atherapeutic agent instead of a dye.

Example 8

The feasibility of incorporating a radiopaque material into a patch ofthe present invention to improve visibility under fluoroscopic imagingwas investigated. In order to render the patch radiopaque underfluoroscopy, it is desirable to incorporate a radiopaque material in thepatch. The radiopaque material may be non-water soluble, such as bariumsulfate, or water soluble, such as iodinated contrast agents. Theseagents can be added to the patch in the same manner as the red dye wasadded in Example 7.

Barium sulfate often is added to medical devices, usually in a range of30 wt %, to render such medical devices radiopaque. It was observed thatadding such agents at similar weight ratios (30%) of barium sulfate oriodinated contrast agent (iopromide) did not result in observableradiopacity of the patch. It is believed that this result obtained dueto the open structure of fibrinogen and the low density of the patch,which was not sufficiently dense to provide the required degree ofradiopacity. It was further observed that much higher quantities of theagents were required to produce an acceptable degree of radiopacity.Surprisingly, however, it was found that a patch as formulated above iscapable of incorporating significant quantities of radiopaquematerials—in some cases multiples of the weight of the fibrinogen andthrombin components, without deterioration in the integrity of thepatch. On the other hand, the flexibility, and therefore deliverabilityof the patch were significantly affected by incorporation of largeamounts of foreign particles.

To resolve the foregoing issue, use of a thin strip of a radiopaquepatch (that contains high concentration of radiopaque material) wastested as a marker on a patch that did not otherwise contain contrastagent. This approach makes use of the adhering capability of the patch,which maintains its integrity even in the presence of the contrastagent. The result is a biodegradable radiopaque marker that can beadhered to any medical device, including the patch.

A first radiopaque patch was prepared using the formulation of Example2, except that 100 mg of barium sulfate was added to the fibrinogensuspension prior to mixing with the thrombin solution. A second patchwas prepared using the formulation of Example 7, except that only 20 μlof color suspension was added to the fibrinogen suspension prior tomixing with the thrombin solution. The patches were dried for 3 hoursunder 30 mm Hg vacuum. A radiopaque marker band was then formed bycutting a rectangular strip having dimensions of 3 mm by 25 mm from thefirst radiopaque patch. The strip was slightly wetted with water andimmediately placed in the middle of a 20 mm by 25 mm rectangular stripof the second patch.

A second radiopaque patch was prepared using the formulation of Example2, except that 200 mg of iopromide powder was added to the fibrinogensuspension prior to mixing with the thrombin solution. A second patchwas prepared using the formulation of Example 7, except that again only20 μl of color suspension was added to the fibrinogen suspension priorto mixing with the thrombin solution. The patches were dried for 3 hoursunder 30 mm Hg vacuum. A radiopaque marker band was then formed bycutting a rectangular strip having dimensions of 3 mm by 25 mm from thesecond radiopaque patch. The strip was slightly wetted with water andimmediately placed in the middle of a 20 mm by 25 mm rectangular stripof the second patch.

The two patches prepared above with radiopaque markers were observedunder fluoroscope and compared to a bare metal stent. Both patchesdemonstrated radiopacity comparable to that of the bare metal stent. Itwas observed that using a non-water soluble contrast agent, such asbarium sulfate, in the marker band is advantageous because it has alonger residence time in the marker. Thus, barium sulfate will notdissolve in blood and therefore should remain in the marker for a longerperiod of time. Over time, the barium sulfate is expected to diffuse outof the fibrin network or be released upon absorption of the fibrin, andthen washed away with the blood stream. Iopromide, on the other hand, iswater soluble and will dissolve in blood contacting the fibrin matrix.Based on the tests conducted, it is expected that the iopromide patchwill lose its radiopacity within 72 hours, while the barium sulfatemarker band is expected to persist for a longer interval.

While various illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

What is claimed is:
 1. A device comprising: a film comprising solidfibrinogen, a plasticizer, and a therapeutic agent, the film configuredto release the therapeutic agent, wherein the film is free-standingwithout a support structure.
 2. The device of claim 1, wherein the filmfurther comprises calcium salt.
 3. The device of claim 2, wherein thecalcium salt comprises calcium chloride.
 4. The device of claim 1,wherein the film comprises two layers, one layer being an adhesivelayer.
 5. The device of claim 1, wherein the film further comprisessolid thrombin mixed with the solid fibrinogen.
 6. The device of claim1, wherein the solid fibrinogen is prepared from unsalted fibrinogen. 7.The device of claim 1, wherein the film has a thickness between 30-500μm.
 8. The device of claim 1, wherein the therapeutic agent comprisesone or more anti-inflammatory agents, anti-allergenic agents,anti-bacterial agents, anti-viral agents, anticholinergic agents,antihistamines, antithrombotic agents, anti-scarring agents,antiproliferative agents, antihypertensive agents, anti-restenosisagents, healing promoting agents, vitamins, proteins, genes, growthfactors, cells or DNA.
 9. The device of claim 1, wherein the therapeuticagent comprises a steroidal anti-inflammatory agent comprising at leastone of 21 acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, any of their derivatives, and combinations thereof. 10.The device of claim 1, wherein the therapeutic agent comprisesfluticasone propionate.
 11. The device of claim 1, wherein the film isformed with a color suspension.
 12. The device of claim 1, wherein thefilm is configured for delivery to a vessel, esophagus, stomach,intestine, bronchus, trachea, urethra, ureter, sinus, ear, or heart. 13.The device of claim 1, wherein the plasticizer comprises polyethyleneglycol selected from PEG 400, PEG 1500, PEG 3000, or PEG
 6000. 14. Thedevice of claim 1, wherein the film is coated with a water-solubleprotective layer.
 15. The device of claim 1, wherein the film furthercomprises a layer of solid fibrinogen.
 16. The device of claim 1,wherein the device is configured to form a fibrin patch.
 17. The deviceof claim 1, wherein the film is configured to become adherent uponexposure to moisture or is adherent prior to exposure to moisture. 18.The device of claim 1, wherein the film is configured to be delivered toa target location using a delivery device.
 19. The device of claim 18,wherein the delivery device comprises an expandable member and the filmis configured to be disposed upon, and delivered by, the expandablemember.
 20. A method of delivering a film to a bodily tissue, the methodcomprising: advancing a film of claim 1 to a target location; andapplying the film to the bodily tissue.